CN1775774A - Process for preparing intermediates for the manufacture of discodermolide and discodermolide analogues - Google Patents

Abstract

The invention relates to a process for the preparation of a substituted alkene of formula (I) wherein R1, R2 and R3 are independently of each other a protecting group for a hydroxy group or hydrogen and R4 is phenyl which is unsubstituted or mono- or disubstituted by alkoxy, which alkene constitutes an intermediate for the preparation of discodermolide and discodermolide analogues.

Description

The intermediates preparation that is used for production discodermolide and discodermolide analogue

The present invention relates to be used for the intermediates preparation of production discodermolide (Discodermolide) and discodermolide analogue, the invention still further relates to the intermediate that in this method process, obtains.

(+)-discodermolide

(+)-discodermolide is researchist isolated a kind of polyketide (polyketide) natural product [S.P.Gunasekera etc., the J.Org.Chem.1990 from the extract of the Spongia deep-sea sponge (Discodermolide dissolute) of ocean by Harbor Branch Oceano-graphic Institution; (disclosed errata is seen J.Org.Chem.1991 to 55:4912-15; 56:1346)].The structure of discodermolide and taxol does not have tangible similarity, but it and the same ability with stabilize microtubules of taxol (active substance among the medicine Taxol ).Confirmed that in clinical practice, taxol can be used for treating the cancer of some type.Discodermolide can combine with tubulin competitively with taxol, and show effectiveness with anti-excess proliferative disease (referring to, as, WO 97/20835).Owing to lack the natural origin that a large amount of compounds are provided, the further exploitation of the analogue of discodermolide or structurally associated is hindered, this is because naturally occurring discodermolide is considerably less and results are produced the biological problem that has logistics.But also lack feasible route of synthesis.Therefore, need a kind of improved production discodermolide and the method for analogue and the new intermediate that is used for this production method, described method and intermediate can be produced the discodermolide of commercial acceptable amount and the analogue of structurally associated.

The present invention relates to a kind of preparation method of alkene of replacement of following formula I:

R wherein ₁, R ₂And R ₃Be hydroxyl protecting group or hydrogen and R independently of one another ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, in described method, by for example using NaBH ₄, LiBH ₄, diisobutyl aluminium hydride, LiB (ethyl) ₃H, Zn, tri-butyl tin hydride or preferably use LiAlH ₄Handle, with the sulphonate reduction of following formula (II)

R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₄Have suc as formula defined implication and R in the I compound ₅Be alkyl or aryl unsubstituted or that alkyl replaces, and subsequently, if necessary, with one, two or all protecting group R ₁, R ₂And R ₃, protecting group R particularly ₁Slough.Be suitable for using LiAlH ₄The reductive reaction conditions is described in for example J.Org.Chem.1980, and 45,2550-2551 or J.Am.Chem.Soc.1951 are in 73, the 2874 pages (wherein described second example).For example, usually can be with NaBH ₄15 ℃ to 100 ℃, use in as the methyl-sulphoxide of 25 ℃ or 85 ℃ or tetramethylene sulfone, and tri-butyl tin hydride usually reflux 1, the existence in sodium iodide in the 2-glycol dimethyl ether (DME) is used down.

In addition, the invention still further relates to the preparation method of alkene of the replacement of a kind of formula I, wherein R ₁, R ₂And R ₃Be hydroxyl protecting group or hydrogen and R independently of one another ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, in described method, at first for example by using LiAlH ₄Handle, with the carboxylicesters reduction of Formula Il I

R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₆Be alkyl or aryl alkyl and R ₄Have suc as formula defined implication in the I compound, and with the alcohol of the following formula I V that obtained

R wherein ₁, R ₂, R ₃And R ₄Have as defined implication in the formula III compound, under reaction conditions known in the art, react with the compound of following formula V,

R ₅SO ₂Hal (V)

R wherein ₅Be the aryl that alkyl or unsubstituted or alkyl replace, and Hal represents halogen, then with the sulphonate of the formula II that obtained for example by using LiAlH ₄Handle and further reduce, wherein R ₁, R ₂, R ₃And R ₄Have defined implication and R in the carboxylicesters as formula III ₅Be alkyl or aryl unsubstituted or that alkyl replaces, and if necessary, by methods known in the art, with one, two or all protecting group R ₁, R ₂And R ₃Slough.

In addition, the invention still further relates to a kind of preparation method of carboxylicesters of formula III, wherein R ₁And R ₂Be hydroxyl protecting group, these protecting groups can be identical or different, R ₃Be hydrogen, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl and R ₆Be the alkyl or aryl alkyl, in described method, with the allyl halide of following formula VI

R wherein ₁And R ₂Having in the carboxylicesters as formula III defined implication and X is halogen, and preferred bromine or iodine reacts in the presence of alkali with the carboxylicesters of following formula VII,

R wherein ₃, R ₄And R ₆Has defined implication in the carboxylicesters as formula III.

The present invention also is particularly related to the method for sulphonate and synthetic this sulphonate of formula II, wherein R ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, preferably alkoxy is mono-substituted, and R ₅Be alkyl or aryl unsubstituted or that alkyl replaces.Preferably in the sulphonate of this formula II, R ₁And R ₂Be identical, R ₁, R ₂And R ₃Be benzyl or silyl protecting group, and R ₅Be low alkyl group or by low alkyl group replace, first-selected mono-substituted phenyl.In a highly preferred embodiment, R ₁And R ₂And R ₃All are t-butyldimethylsilyl, R ₄Be unsubstituted or by the mono-substituted phenyl of methoxyl group, and R ₅It is methyl or by the mono-substituted phenyl of low alkyl group.

In addition, the present invention also is particularly related to a kind of carboxylicesters of formula III, wherein R ₁And R ₂Be hydroxyl protecting group, these protecting groups can be identical or different, R ₃Be hydroxyl protecting group or hydrogen, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, and R ₆It is the alkyl or aryl alkyl.In an embodiment preferred of the present invention, contain identical radicals R in the carboxylicesters of formula III ₁And R ₂, R ₁, R ₂And R ₃Be silyl protecting group and R ₆It is low alkyl group.

In addition, the present invention also is particularly related to the alcohol of formula IV, wherein R ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, and R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl.

In addition, the invention still further relates to the carboxylicesters of formula VII, wherein R ₃Be hydrogen, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, and R ₆It is the alkyl or aryl alkyl.

In addition, the invention still further relates to following formula VIII De oxazolidone

Wherein Ph represents phenyl, and R ₁And R ₂Be silyl protecting group, hydrogen or unsubstituted or replaced or dibasic benzyl, perhaps R independently of one another by the lower alkoxy list ₁And R ₂Represent the methylene radical (methyliden) that phenyl replaces together, described phenyl is replaced by the lower alkoxy list or is dibasic, and relates to following formula I X De oxazolidone

Wherein Ph represents phenyl and R ' and R ₂Be that silyl protecting group, hydrogen or unsubstituted or lower alkoxy list replace or disubstituted benzyl independently of one another, condition is radicals R ' and R ₂The two one of be the silyl protecting group.

In addition, the invention still further relates to δ-penta lactol of following formula X

R wherein ₂Be hydroxyl protecting group, and relate to the alcohol of following formula XI

R wherein ₁And R ₂All represent the silyl protecting group.

In addition, the invention still further relates to the sulphonate of formula II, the carboxylicesters of formula III, the alcohol of formula IV or the purposes of carboxylic acid (all as defined above) in the method for producing (+)-discodermolide or discodermolide analogue of formula VII.

In addition, the invention still further relates to the preparation method of the ether of following formula XXVI:

R wherein ₁Be that the alkoxy list replaces or dibasic benzyl R ₂Expression hydroxyl protecting group or hydrogen, and R ₁₀It is N-oxazolidinyl unsubstituted or that replaced by alkyl, benzyl or phenyl; OR _e, R wherein _eBe alkyl or benzyl; Or N (R _a) ₂, R wherein _aBe alkyl or benzyl, in described method, with the compound of following formula XXVII

Radicals R wherein ₂And R ₁₀Suc as formula defining in the XXVI compound, with the trichlorine iminodiacetic acid ester of following formula XVII

Wherein m is 1 or 2 and alkoxyl group lower alkoxy preferably; methoxyl group particularly; in the presence of the trifluoromethanesulfonic acid samarium of catalytic amount or Ytterbiumtriflate; in suitable solvent, particularly methylene dichloride; in-15 ℃ to+15 ℃, preferred-5 ℃ to+5 ℃, particularly reaction under about 0 ℃; subsequently, if necessary, with protecting group R ₂Slough.

In scope disclosed by the invention,, above reach hereinafter used General Definition and preferably have following implication if there is not other indication:

Prefix " rudimentary " is meant that corresponding part preferably has maximum 7 (comprising 7) carbon atoms, more preferably maximum 4 carbon atoms.

Be meant can be under alkalescence or neutrallty condition for Ding Yi " hydroxyl protecting group " herein; promptly in the medium of pH 〉=7 by the protecting group of being sloughed; and particularly unsubstituted or alkoxy, particularly lower alkoxy, preferred methoxyl group list replace or dibasic benzyl, perhaps silyl protecting group more especially.The group that the silyl protecting group is made up of Siliciumatom, described Siliciumatom have free valency and have three groups that are selected from aryl, alkyl and arylalkyl.The silyl protecting group is trialkylsilkl-or diaryl-alkyl silyl protecting group particularly, as triethylsilyl, diethyl sec.-propyl silyl, and it is most preferred that t-butyldimethylsilyl.

Alkyl is low alkyl group preferably, and it can be a straight or branched, and particularly ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl or, preferred, the methyl or the tertiary butyl.

Alkoxyl group is lower alkoxy preferably, as oxyethyl group or tert.-butoxy, and it is most preferred that methoxyl group.

Aryl is C particularly ₆-C ₁₀Aryl, especially phenyl or naphthyl.

Arylalkyl is benzyl particularly.

Halogen is fluorine, chlorine, bromine or iodine preferably.

Any reference about other document or public publication among the application is meant to be introduced corresponding document or public publication in the application's disclosure as a reference.

The alkene of the replacement of formula I is the suitable intermediate that is used for producing (+) discodermolide and discodermolide analogue as defined above.

Specifically, can be by compound being used the mixture process of trifluoroacetic acid at tetrahydrofuran (THF) and water, wherein all radicals R ₁, R ₂And R ₃The alkene of replacement that all is the formula I of t-butyldimethylsilyl optionally is transformed into wherein R ₁Be hydrogen and R ₂And R ₃It all is the compound of the formula I of t-butyldimethylsilyl.Subsequently, can be by with compound and the suitable reagent of formula I, as 4-Methochloride or bromide at Ag ₂Under the existence of O, reaction at room temperature in The suitable solvent such as dimethyl formamide is with R ₁Hydrogen atom in the group replaces to the 4-methoxy-benzyl.Other suitable reagent and reaction conditions are described in T.W.Greene, and " protecting group in the organic synthesis (ProtectiveGroups in Organic Synthesis) ", Wiley is in 1981, the 29 pages in New York and the reference quoted thereof.It is most preferred that, by inciting somebody to action wherein R ₁Be the alkene of replacement of formula I of hydrogen and the compound of following formula XVII,

Wherein m is 1, in The suitable solvent such as methylene dichloride, in the existence reaction down of suitable catalyzer such as trifluoromethanesulfonic acid samarium or Ytterbiumtriflate, with R ₁Hydrogen atom in the group replaces to 4-methoxyl group-benzyl.

People such as Amos B.Smith III are at J.Am.Chem.Soc.2000, and 122, confirmed the wherein R of above gained among the 8654-8664 ₁Be 4-methoxyl group-benzyl, R ₂And R ₃Be t-butyldimethylsilyl and R ₄The alkene of replacement that is the formula I of 4-p-methoxy-phenyl is applicable to production (+)-discodermolide, in the disclosure document, the method (compound " AB " in the scheme 9 of the 8658th page scheme 7 and the 8659th page) that the alkene of the replacement of this formula I is transformed into (+)-discodermolide is disclosed.

R wherein ₁, R ₂And R ₃Be hydroxyl protecting group or hydrogen and R independently of one another ₄Be unsubstituted or the alkoxy list replaces or the formula of dibasic phenyl [the alkene of replacement, by the sulphonate of formula II (R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₄Have suc as formula defined implication and R in the I compound ₅Be alkyl or aryl unsubstituted or that alkyl replaces) by using LiAlH ₄Under condition known in the art with the also preparation originally of this sulphonate, for example, by-100 to-25 ℃, add LiAlH as the solution of-78 ℃ of downdraft mode II compounds in suitable solvent ₄Prepare.The suitable solvent is, as, diethyl ether, diglyme and particularly tetrahydrofuran (THF).Perhaps, can use NaBH ₄In polar aprotic solvent, use LiEt ₃BH, use Bu ₃SnH-NaI or with NaI and Zn 1, finish reduction reaction in the 2-glycol dimethyl ether.

With the carboxylicesters of formula III (R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₆Be alkyl or aryl alkyl and R ₄Being unsubstituted or the alkoxy list replaces or dibasic phenyl) reduction forms the alcohol (R wherein of formula IV ₁To R ₄Have as defined implication in the formula III compound) be known in the art and can be by using such as following reagent: LiBH ₄, (isobutyl-) ₂AlH, lithium triethylborohydride, BH ₃-S (methyl) ₂In the tetrahydrofuran (THF) that refluxes, triethoxyl silane or sodium finishes in ethanol.Preferably, reaction is by using LiAlH ₄Finish in The suitable solvent such as tetrahydrofuran (THF).

With the alcohol of formula IV (R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, and R ₄Be unsubstituted or the alkoxy list replaces or dibasic phenyl) with the compound of formula V (R wherein ₅Be that aryl and the Hal that alkyl or unsubstituted or alkyl replace represents halogen) under condition known in the art, react, form the sulphonate (R wherein of formula II ₁, R ₂, R ₃And R ₄Have defined implication and R in the alcohol suc as formula IV ₅Be alkyl or aryl unsubstituted or that alkyl replaces).Preferably, be reflected under the existence such as the alkali of pyridine, in suitable inert solvent, carry out.

Also can be with the compound of formula III (R wherein ₁And R ₂Be hydroxyl protecting group, these protecting groups can be identical or different, R ₃Be hydrogen and R ₆Be alkyl or aryl alkyl and R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl) by single bottle of synthesis mode reaction, promptly do not separate intermediate as herein described, form the compound of formula I, wherein R ₁, R ₂And R ₄Have with the formula III compound in identical implication and R ₃It is hydroxyl protecting group.

The preparation of formula VII compound

For example, by aldehyde with following formula XII

R wherein ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, with the compound of following formula XIII

CH ₃CO ₂R ₆ (XIII)

R wherein ₆It is the alkyl or aryl alkyl, in The suitable solvent, particularly tetrahydrofuran (THF), in highly basic, preferred lithium diisopropylamine (LDA) and the optional N that exists, N, N ', N ', N ", N is " under the existence of HMPA (HMPTA) and Chiral Media or catalyzer, at-100 ℃ to-50 ℃, as-78 ℃ of reactions down, the compound of production VII, wherein R ₃Be hydrogen, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl and R ₆It is the alkyl or aryl alkyl.

The aldehyde of formula XII (radicals R wherein ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl) be that oxidation prepares as Swern with conventional oxidizing reaction by the alcohol with following formula XIV,

R wherein ₄Have suc as formula defined implication among the XII.The oxalyl chloride that preferably will be dissolved in suitable solvent such as the methylene dichloride mixes with methyl-sulphoxide in being dissolved in same solvent, then the alcohol of adding formula XIV under-50 ℃ to-100 ℃ as-78 ℃ temperature approximately.Subsequently, under uniform temp, add suitable alkali, particularly diisopropylethylamine.

The alcohol of formula XIV (R wherein ₄Be unsubstituted or the alkoxy list replaces or dibasic phenyl) be by the acetal of formula VIII (R wherein ₁And R ₂-play the methylene radical that the expression phenyl replaces, described phenyl is that the alkoxy list replaces or dibasic) by with itself and LiAlH ₄In The suitable solvent, particularly tetrahydrofuran (THF), in approximately-50 ℃ to-100 ℃ as-78 ℃ of following reactions prepare.

The acetal of formula VIII (R wherein ₁And R ₂Represent the methylene radical that phenyl replaces together, described phenyl is alkoxy list replacement or dibasic) can obtain by two different synthesis paths:

(a) at first, with the aldehyde of following formula XV

Wherein n is 1 or 2, with the ketone of following formula XVI

Wherein Ph represents phenyl, in The suitable solvent such as methylene dichloride, and under existence greater than the dibutyl boryl triflate of equimolar amount and alkali, preferred diisopropylethylamine ,-15 ℃ to+15 ℃ as 0 ℃ of reaction down, formation following formula VIII De oxazolidone

R wherein ₁Be that the alkoxy list replaces or dibasic benzyl, and R ₂Be hydrogen.

And then, described formula VIII De oxazolidone is transformed into wherein R ₂It is for example respective compound of the tertiary butyl-dimetylsilyl formula VIII of the hydroxyl protecting group that to slough by hydrogenolysis; this can by with the reagent react that can introduce this protecting group; for example by with the tertiary butyl-dimetylsilyl-triflate in The suitable solvent such as toluene, chloroform or methylene dichloride; as 2, the existence of 6-lutidine reaction is down finished in alkali.

With the compound hydrogenolysis that obtains, for example, obtain wherein R by this compound and hydrogen reaction and use in the presence of such as the catalyzer of palladium carbon is pure as solvent with the formula VIII of silyl protection ₁Be hydrogen and R ₂It is the formula VIII compound of hydroxyl protecting group as defined above.

In another embodiment of the invention, by the compound of following approach preparation formula VIII, wherein R ₁Be hydrogen and R ₂It is hydroxyl protecting group.

At first, formula XVI compound and methacrylaldehyde are in The suitable solvent such as methylene dichloride as defined above, under existence greater than the dibutyl boryl triflate of equimolar amount and alkali, preferred diisopropylethylamine,-15 ℃ to-90 ℃ preferred-75 to-80 ℃ of reactions down approximately, form following formula XVIII De oxazolidone

Wherein Ph represents phenyl and R ₂Be hydrogen.

Then, described formula XVIII De oxazolidone further is transformed into wherein R ₂It is the respective compound of the formula XVIII of hydroxyl protecting group such as the tertiary butyl-dimetylsilyl; this can by with the reagent react that can introduce this protecting group; for example by with the tertiary butyl-dimetylsilyl-triflate in The suitable solvent such as toluene, chloroform or methylene dichloride; as 2, the existence of 6-lutidine reaction is down finished in alkali.

At last, with the wherein R that is obtained ₂Be the formula XVIII De oxazolidone and 1,1 of hydroxyl protecting group, 2-trimethylammonium propyl group borine or preferred 9-BBN (9-boron mix dicyclo [3.3.1]-nonane) react in-5 ℃ to+35 ℃ times in The suitable solvent such as tetrahydrofuran (THF), form wherein R ₁Be hydrogen and R ₂It is the compound of the formula VIII of hydroxyl protecting group.

Then, incite somebody to action wherein R ₁Be hydrogen and R ₂Be the compound of formula VIII of hydroxyl protecting group and the trichlorine iminodiacetic acid ester of following formula XVII

Wherein m is 1,2 or 3, in The suitable solvent such as methylene dichloride, and in the existence contact down of suitable catalyzer such as trifluoromethanesulfonic acid samarium or Ytterbiumtriflate, so that form the compound of formula VIII, R wherein ₁Be that the alkoxy list replaces or dibasic benzyl and R ₂It is the hydroxyl protecting group that to slough by hydrogenolysis.

Then, with the compound of this formula VIII further with can slough protecting group R ₂Reagent keeping radicals R ₁React under the constant condition, this condition is known in the art.For example, if R ₂Be the tertiary butyl-dimetylsilyl, the reagent that then can slough this group can be aqueous hydrogen fluoride solution, it can be mixed in acetonitrile or other suitable low alkyl group cyanogen with formula VII compound.The compound of this reaction acquisition formula VII, wherein R ₁Be that the alkoxy list replaces or dibasic benzyl and R ₂Be hydrogen.

By with the compound of this formula VII (R wherein ₁Be that the alkoxy list replaces or dibasic benzyl and R ₂Be hydrogen) handle with DDQ (2,3-two chloro-5,6-dicyano-1,4-benzoquinones), obtain the required acetal (R wherein of formula VIII ₁And R ₂Represent the methylene radical that phenyl replaces together, described phenyl is that the alkoxy list replaces or dibasic), this reaction can be in The suitable solvent such as methylene dichloride, in-10 ℃ to+10 ℃, preferably carries out under about 0 ℃.

(b) also can (wherein Ph represents phenyl and R with the oxazolidone as the above-mentioned formula XVIII that obtains ₂Be hydrogen) with 1,1,2-trimethylammonium propyl group borine or preferred 9-BBN (9-boron mix dicyclo [3.3.1] nonane) are in The suitable solvent such as tetrahydrofuran (THF), react down and need not the prior hydroxyls that exist in compound and protect in-5 ℃ to+35 ℃.Reaction product is R wherein ₁And R ₂It all is the compound of the formula VIII of hydrogen.Can be further in The suitable solvent such as methylene dichloride, under such as 15 ℃ to 30 ℃ temperature, in the presence of suitable acid such as toluenesulphonic acids, camphorsulfonic acid or preferred macroporous resin 15, with the compound reaction of following formula XIXa with this product

Wherein q is 0,1 or 2, and R _xAnd R _yBe low alkyl group, form the required acetal (R wherein of formula VIII ₁And R ₂Represent the methylene radical that phenyl replaces together, described phenyl is alkoxyl group list replacement or disubstituted).

Perhaps, also can by with the compound of following formula XIXb

Wherein q is 0,1 or 2, in The suitable solvent such as methylene dichloride or benzene, in under the reaction conditions known in the art, particularly under the reflux temperature at solvent, randomly can with the reagent of the water reaction that produces in the reaction process in the presence of, in the presence of in dicyclohexylcarbodiimide, react, wherein R ₁And R ₂The compound that all is the formula VIII of hydrogen is transformed into wherein R ₁And R ₂Represent that together methylene radical and described phenyl that phenyl replaces are the acetals of the replacement of alkoxy list or dibasic formula VIII.

By R wherein ₁And R ₂The formula VIII compound that all is hydrogen begins, and obtains wherein R ₁And R ₂Representing that together methylene radical that phenyl replaces and described phenyl are that the alkoxy list replaces or the another kind of path of the acetal of dibasic formula VIII, is with R wherein ₁And R ₂All be the formula VIII compound of hydrogen and the compound and 2 of following formula XIXc, 3-two chloro-5,6-dicyano-1,4-benzoquinones (DDQ) are in The suitable solvent such as methylene dichloride, in reaction conditions known in the art reaction down

Wherein q is 0,1 or 2.

The δ-Wu Neizhi of the δ of following formula X-penta lactol and following formula XX

The R in the two wherein ₂All being hydroxyl protecting group, is the suitable starting material of synthesis type VI and VII compound.For example, can be with R wherein ₂Be formula (XX) compound of hydroxyl protecting group and LiOH and can introduce hydroxyl protecting group R ₂Reagent in The suitable solvent, react the compound that obtains following formula XXV

R wherein ₁And R ₂Be hydroxyl protecting group independently of one another.Then, this compound is reduced with reagent known in the art, for example use NaBH ₄And AlCl ₃In diglyme, reduce, use BH ₃In tetrahydrofuran (THF), reduce, use LiAlH (O-methyl) ₃In tetrahydrofuran (THF), reduce, use AlH ₃In diethyl ether, reduce, use LiAlH ₄Reduce in diethyl ether or reduce in tetrahydrofuran (THF) with diisobutyl aluminium hydride, all scenario all carries out under known condition, so that generate the compound of following formula XI

R wherein ₁And R ₂Have suc as formula defined implication in the XXV compound.

By lactone and DIBAH (diisobutyl aluminium hydride) reaction under about-85 to-70 ℃ in The suitable solvent such as tetrahydrofuran (THF), obtain the lactol of described formula X with described formula XX.

R wherein ₂The lactone that is the formula XX of hydroxyl protecting group is R wherein ₁Be hydrogen and R ₂Be formula VIII compound and the potassium alcoholate of catalytic amount such as the reaction product that potassium tert.-butoxide reacts under about-10 ℃ to+10 ℃ as 0 ℃ in The suitable solvent such as tetrahydrofuran (THF) of hydroxyl protecting group.

Perhaps, can prepare wherein R by following synthesis path ₂Be the lactone of the formula XX of hydroxyl protecting group:

At first, with the aldehyde (wherein n is 1 or 2) of formula XV and the ketone of following formula XXI

Wherein Ph represents phenyl, in The suitable solvent such as methylene dichloride, and under existence greater than the dibutyl boryl triflate of equimolar amount and alkali, preferred diisopropylethylamine ,-15 ℃ to+15 ℃ as 0 ℃ of reaction down, formation following formula I X De oxazolidone

Wherein Ph represents phenyl, and R ' is unsubstituted or the alkoxy list replaces or dibasic benzyl and R ₂Be hydrogen.

Then, this formula IX De oxazolidone further is transformed into wherein R ₂It is for example respective compound of the formula IX of the tertiary butyl-dimetylsilyl of the hydroxyl protecting group that to slough by hydrogenolysis; this transformation by with the reagent react that can introduce described protecting group; for example by with the tertiary butyl-dimetylsilyl-triflate in The suitable solvent such as toluene, chloroform or methylene dichloride; as 2, the existence of 6-lutidine reaction is down finished in alkali.

With the protection of the formula IX that obtained the compound hydrogenolysis, for example, obtain wherein R by with the reaction and use alcohol in the presence of such as the catalyzer of palladium carbon of this compound and hydrogen as solvent ₁Be hydrogen and R ₂It is the compound of the formula IX of hydroxyl protecting group as defined above.

By with H ₂O ₂In the mixture of suitable solvent such as tetrahydrofuran (THF) and water, in the presence of LiOH in-15 ℃ to+15 ℃ as 0 ℃ reaction down, by R wherein ₁Be hydrogen and R ₂The formula IX compound that is the hydroxyl protecting group that can not slough by hydrogenolysis obtains required lactone XX.

The preparation of the allyl halide of formula VI

R wherein ₁And R ₂Be hydroxyl protecting group, these protecting groups can be identical or different, and X is halogen, obtain by following reactions steps:

The wherein Ph that obtains is as mentioned above represented phenyl and R wherein ₁And R ₂The formula VIII De oxazolidone that all is hydrogen is transformed into wherein R ₁And R ₂All be that hydroxyl protecting group (can not be sloughed under the reaction conditions of this protecting group in the reactions steps of the required compound that obtains formula VI subsequently; the silyl protecting group of hydroxyl preferably; the tertiary butyl-dimetylsilyl for example) respective compound of formula VIII; this transformation by with the reagent react that can introduce this protecting group; for example by with the tertiary butyl-dimetylsilyl-triflate in The suitable solvent such as toluene, chloroform or methylene dichloride in alkali as 2, the existence of 6-lutidine down reaction is finished.

Then, with formula VIII compound and suitable original reagent, the preferred LiBH of going back ₄, in the mixture of The suitable solvent such as tetrahydrofuran (THF) and water,, obtain the alcohol of following formula XI in-5 ℃ to+30 ℃ reactions down approximately

R wherein ₁And R ₂All represent hydroxyl protecting group, can not slough under the reaction conditions of this protecting group in the reactions steps of the required compound that obtains formula VI subsequently, preferably the silyl protecting group.

Then, by alcohol,, obtain the corresponding aldehyde of following formula XXII preferably by the Swern oxidation with suitable reagent oxidation-type XI

R wherein ₁And R ₂Such as in the following formula XI compound definition.Carry out the Wittig olefination with the phosphonic acid ester of following formula XXIII

R wherein ₇Be alkyl or aryl alkyl and R ₈And R ₉Be unsubstituted or independently of one another, obtain the α of following formula XXIV, the beta-unsaturated carboxylic acid ester by the alkyl that halogen, preferred fluorine replace

R wherein ₁And R ₂Such as in the following formula XI compound definition and R ₇It is the alkyl or aryl alkyl.Reaction preferably in tetrahydrofuran (THF), is carried out under the existence of alkaline hexamethyldisilazane potassium and hexaoxacyclooctadecane-6-6.

Then, described formula XXIV compound and DIBAH or other reagent, the particularly reagent that carboxylicesters can be transformed into alcohol disclosed herein are reacted in The suitable solvent, for example, when using DIBAH, in methylene dichloride, react, form the vinyl carbinol of formula VI, wherein R ₁And R ₂Be hydroxyl protecting group, these protecting groups can be identical or different, and X is a hydroxyl.

At last, by with iodine in the presence of triphenylphosphine and imidazoles, in the mixture of The suitable solvent such as diethyl ether and low alkyl group nitrile, react, the vinyl carbinol of formula VI is changed the required allyl halide of accepted way of doing sth VI, preferred allyl group iodate thing.

It will be appreciated by those skilled in the art that the above-mentioned reaction conditions that provides can replace with similar reaction conditions on the principle known in the art.In addition; those skilled in the art know the suitable hydroxyl protecting group that can replace used protecting group in the following specific embodiment; and these groups are connected to above reach on the free hydroxyl group that exists among hereinafter described compound, particularly formula I, IV, VIII or the IX, and how this group is sloughed if necessary.In addition, those skilled in the art can select to be suitable for above reaching the special reaction condition of hereinafter described reactions steps (briefly having described reaction therein).All these reaction conditionss all belong in the scope of the present invention.

Hydroxyl for example is described in the canonical reference works with protecting group protection, protecting group itself and their scission reaction, as J.F.W.McOmie, " protecting group in the organic chemistry (ProtectiveGroups in Organic Chemistry) ", Plenum Press, London and New York 1973; T.W.Greene, " protecting group in the organic synthesis (Protective Groups in Organic Synthesis) ", Wiley, New York 1981; " peptide (The Peptides) ", the 3rd volume (editor: E.Gross and J.Meienhofer), Academic Press, London and New York 1981; " Methoden derorganischen Chemie " (organic chemistry method), Houben-Weyl, the 4th edition, 15/I volume, Georg Thieme Verlag, Stuttgart 1974; H.-D.Jakubke and H.Jescheit, " Aminos  uren; Peptide; Proteine " (amino acid, peptide, protein), Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982 and Jochen Lehmann, " Chemieder Kohlenhydrate:Monosaccharide und Derivate " (carbohydrate chemistry: monose and derivative), Georg Thieme Verlag, Stuttgart 1974.

Following examples only are illustrative, and the scope that does not limit the present invention in any way.Starting material be can buy obtain or can prepare by method as described below.

Abbreviation:

Aqu. aqueous

9-BBN 9-boron dicyclo [3.3.1] nonane of mixing

The salt solution saturated nacl aqueous solution

The bu butyl

The DIBAH diisobutyl aluminium hydride

DDQ 2,3-two chloro-5,6-dicyano-1,4-benzoquinones

The DMSO methyl-sulphoxide

The Et ethyl

The EtOAc ethyl acetate

The FC flash chromatography

H hour

HMPA N, N, N ', N ', N ", N " HMPA

The HRMS high resolution mass spectrum

The K kelvin absolute scale

KHMDS hexamethyldisilazane potassium

Min minute

M.p. fusing point

The Me methyl

The MS mass spectroscopy

MS (EI) electrospray ionization mass spectrometry

The Ph phenyl

PTLC preparative thin-layer chromatography method

The RT room temperature

Sat. saturated

The TBDMS tertiary butyl-dimetylsilyl

The TBME t-butyl methyl ether

The TBSOTf tertiary butyl-dimetylsilyl-triflate

The Tf triflate

THF hydrogen furans

Abbreviation in the NMR spectroscopic data

The b broad peak

D is bimodal

The J coupling constant

The m multiplet

The q quartet

S is unimodal

The t triplet

The per 1,000,000/umber of ppm

Embodiment 1: (4R)-the 4-benzyl-(N)-[(2R, 3S, 4S)-and 5-(4-methoxyl group benzyloxy base)-2,4-dimethyl-3-(tertiary butyl-dimethylsilane oxygen base)-pentanoyl]-oxazolidine-2-ketone

(1.36g 3.1mmol) is dissolved in 10mL CH under argon atmosphere with the alcohol that derives from step 1.1 ₂Cl ₂In and be cooled to 0 ℃.Add 2,6-lutidine (0.49mL, 4.0mmol, 1.3 equivalents) then drips TBSOTf (0.78mL, 3.4mmol, 1.1 equivalents).Reaction mixture was stirred 30 minutes, be poured on the frozen water and use hexane extraction.Organic layer with 1N HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, then with dried over mgso and vacuum concentration, is obtained the title compound of colorless oil.

Step 1.1: with (R)-4-benzyl-(N)-Bing Xian Ji oxazolidine-2-ketone (Aldrich, 336mg, 1.44mmol) 1.0M Bu of the solution in the 3.0mL methylene dichloride ₂(1.6mL 1.6mmol) is handling under argon atmosphere under 0 ℃ the solution of BOTf.In the red-brown mixture of gained, add 0.30mL (1.7mmol) diisopropylethylamine, obtain colourless, clear soln, it was stirred 1 hour down at 0 ℃.Slowly add down at-78 ℃ then and be dissolved in 1.5mL CH ₂Cl ₂In (S)-3-(4-methoxyl group benzyloxy base)-2-methyl-propionic aldehyde (Aldrich, 300mg, 1.44mmol).Reaction mixture was stirred 60 minutes under this temperature and stirred 45 minutes down at 0 ℃.Add the phosphate buffered saline buffer of pH 7.0, then with TBME extraction (3 times).With the organic layer that merges with saturated NaCl solution washing, with dried over mgso and vacuum concentration.Be dissolved in resistates in the 5mL methyl alcohol again and use 2mL H ₂O ₂The aqueous solution (30%) is handled down at 0 ℃.Stir after 1 hour, vacuum is removed volatile matter and water is extracted (3 times) with TBME.With the saturated NaHCO of organic layer that merges ₃With the salt water washing, with dried over mgso and vacuum concentration.Through chromatogram purification (SiO ₂, heptane/ethyl acetate 2: 1) after obtain the required alcohol of colorless oil.

Embodiment 2: (4R)-the 4-benzyl-(N)-[(2R, 3S, 4S)-and 5-hydroxyl-2,4-dimethyl-3-(tertiary butyl-dimethylsilane oxygen base)-pentanoyl]-oxazolidines-2-ketone

Under 23 ℃, the solution of TBDMS ether in 3.0mL methyl alcohol that 132mg (0.24mmol) is derived from embodiment 1 is in the presence of catalytic amount Pd/C, and hydrogenation is 6 hours under 1 crust atmosphere of hydrogen.After reaction mixture filtered by the cellflock pad, with ethyl acetate washing 3 times, vacuum concentration and carry out flash chromatography (SiO ₂, hexane/EtOAc 1: 1), obtain the title compound of colorless oil.

¹H-NMR(CDCl ₃，300MHz，300K)δ7.32-7.05(m，5H)，4.62-4.52(m，1H)，4.12(d，J＝6.0Hz，1H)，4.12-4.0(m，2H)，3.50(dd，J＝12.0，5.3Hz，1H)，3.42(dd，J＝12.0，6.8Hz，1H)，3.19(dd，J＝13.5，3.7Hz，1H)，2.70(dd，J＝13.5，9.0Hz，1H)，1.9-1.85(m，1H)，1.65-1.45(br?m，1H)，1.20(d，J＝8.3Hz，3H)，0.92(d，J＝7.5Hz，3H)，0.88(s，9H)，0.05(s，3H)，0，00(s，3H)。MS(EI)m/z?458(100，[M+Na] ⁺)。

Embodiment 3: (1RS, 2R, 3S, 4S)-and 5-hydroxyl-2, the 4-dimethyl-3-tertiary butyl-dimethylsilane oxygen base-δ-penta lactol

With the lactone of step 3.1 (1.00g, 3.87mmol) be dissolved in the 40mL toluene and at-78 ℃ down with 10 minutes times interpolation 3.10mL (4.65mmol) DIBAH (toluene solution of 1.5M).At-78 ℃ after following 30 minutes, make the reaction mixture stopped reaction by adding 2mL MeOH.The mixture of gained is poured over saturated NH ₄On the Cl aqueous solution and make two separate.The waterbearing stratum is extracted (3 times) with EtOAc.The organic phase that merges is used 10%H successively ₂SO ₄The aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing with dried over mgso and vacuum concentration, obtain the title compound of colorless oil.

¹H-NMR (CDCl ₃, 300MHz, 300K, the mixture of anomer, ratio=4.2: 1.0) and main anomer: δ 4.68 (br s, 1H); 3.72 (dd, J=11.2,0.8Hz, 1H); 3.62 (br m, 1H), 3.32 (dd, J=11.2,5.6Hz, 1H); 2.02-1.85 (two m, 2H), 0.93 (d, J=7.1Hz, 3H), 0.87 (s, 9H), 0.75 (d, J=7.5Hz, 3H), 0.04 (s, 3H), 0.01 (s, 3H); Accessory anomer: δ 5.00 (d, J=1.9Hz, 1H), 3.80-3.67 (m, 1H, because of a signal from main anomer unclear), 3.43 (dd, J=11.3,7.1Hz, 1H), and 2.05-1.80 (two m, 2H), 0.90 (d, J=7.3Hz, 3H), 0.84 (s, 9H), 0.82 (d, J=7.5Hz, 3H), 0.00 (s, 3H),? 0.3 (s, 3H); MS (EI) m/z244 (7, [M-O]] ⁺), 204 (55, [M-C (CH ₃) ₃] ⁺), 145 (100, [M-Si (CH ₃) ₂(CH ₃) ₃] ⁺).

Step 3.1: (43mg is 0.1mmol) at 1.5mL THF/H will to derive from the alcohol of embodiment 2 ₂Solution among the O (3: 1) is following to 40 μ l (0.4mmol, 4.0 equivalents) H at 0 ℃ ₂O ₂(30%) handles, then handle with 8mg (0.2mmol, 2.0 equivalents) LiOH monohydrate.Stir after 40 minutes, add the Na of 0.3mL 1.5M ₂SO ₃The aqueous solution.Extract with the saturated sodium bicarbonate aqueous solution termination reaction and with TBME.With the saturated NaHCO of ether layer ₃Twice of solution washing.The aqueous extract that merges is also used ethyl acetate extraction (3 times) with 1N HCl acidifying (pH3).Organic layer is merged, with dried over mgso and vacuum concentration, obtain the required lactone of colourless crude product buttery, it contains Yi Xie oxazolidone as major impurity. ¹H-NMR(DMSO-d ⁶，400MHz，300K)δ4.20(dd，J＝11.5，4.0Hz，1H)，4.07(dd，J＝11.5，8.4Hz，1H)，3.83(dd，J＝5.3，2.8Hz，1H)，2.47(qd，J＝7.8，5.3Hz，1H)，2.28-2.15(m，1H)，1.20(d，J＝7.8Hz，3H)，0.90(d，J＝7.1Hz，3H)，0.88(s，9H)，0.09(s，3H)，0.08(s，3H)。MS(EI)m/z?539(30，[M+2Na] ⁺)，322(55，[M+CH ₃CN] ⁺)。

Embodiment 4: (4R)-and 4-sec.-propyl-5, the 5-phenylbenzene-(N)-[(2R, 3S, 4S)-and 5-hydroxyl-2,4-dimethyl-3-(tertiary butyl-dimethylsilane oxygen base)-pentanoyl]-oxazolidines-2-ketone

Under 0 ℃, in the 60mL THF solution of the TBDMS ether of 7.67g (14.7mmol) step 4.2, under argon atmosphere, be added on 3.59g (29.4mmol) 9-BBN among the 50mL THF.At 0 ℃ after following 15 minutes, make reaction mixture be warming up to room temperature and stirred 5 hours.Mixture is cooled to 0 ℃ and with the water-bearing phosphate salt buffer of 1: 1 (v/v) EtOH/THF, the pH 7 of the 19.4mL that respectively does for oneself and 35% aqueous hydrogen peroxide solution termination reaction again.After 30 minutes, allow solution be warming up to room temperature once more and stirred 15 hours.Add heptane (150mL) and 20%NaHSO ₃The aqueous solution (120mL) and with the waterbearing stratum with heptane extraction (2 * 100mL).With the organic layer that merges with the saturated sodium-chloride water solution washing (1 * 100mL), with dried over mgso, filter and vacuum concentration.By purification by flash chromatography (SiO ₂, hexane/AcOEt 4: 1), obtain the title compound of colorless oil, its crystallization when depositing for 4 ℃. ¹H-NMR (CDCl ₃, 300MHz, 300K) δ 7.55-7.15 (4m, 10H), 5.27 (d, J=3.5Hz, 1H), 3.95 (dd, J=9.4,2.5Hz, 1H), 3.76 (qd, J=9.4,6.9Hz, 1H), 2.91 (dd, J=12.0,4.9Hz, 1H), 2.49 (dd, J=12.0,7.5Hz, 1H), 1.79 (septet, J=6.8,3.5Hz, 1H), and 1.72-1.65 (br s, 1H), 1.33-18 (m, 1H), 1.23 (d, J=6.9Hz, 3H), 0.83, (d, J=6.8Hz, 3H), 0.81 (s, 9H), 0.72 (d, J=6.8Hz, 3H), 0.58 (d, J=7.1Hz, 3H), 0.00 (s, 6H).

Make the lactone that with the following method title compound is changed into step 3.1:

(2.08g 3.85mmol) is dissolved among the 40mL THF, and at the solution (the THF solution of 1.5M, 77 μ L, 77 μ Mol) that adds t-BuOK under 0 ℃ under argon atmosphere with title compound.With this clarification, colourless solution stirring 1 hour and be warming up to the highest 23 ℃.Form white precipitate.Reaction mixture is diluted and filtration with the 50mL hexane.Resistates washs with saturated sodium-chloride water solution.Collect filtrate and be separated into two-layer.Organic layer is concentrated with dried over mgso and partial vacuum.Form white precipitate in the concentration process.With the mixture filtration and with resistates 5mL hexane wash.Collect filtrate and vacuum concentration, obtain the pure lactone of the step 3.1 of colorless oil, it solidifies when depositing for 4 ℃, and formation m.p. is 53-54 ℃ a solid.

Step 4.1: with the 30mL CH of 14.9mL (87mmol, 1.45 equivalents) diisopropylethylamine ₂Cl ₂Solution under argon atmosphere in 10 minutes, using 1.0M Bu under-5 ℃ ₂The CH of BOTf ₂Cl ₂Solution (78mL, 78mmol, 1.3 equivalents) is handled, then in used (R)-4-sec.-propyl-5,5-phenylbenzene propionyl base oxazolidine-2-ketone (20.2g, 60mmol under-78 ℃ in 15 minutes; According to T.Hintermann, D.Seebach, Helv.Chim.Acta 1998,81,2093 the preparation) 60mL CH ₂Cl ₂Solution-treated obtains clear orange solution.At-78 ℃ after following 10 minutes, allow solution be warming up to 0 ℃ and stirred 1 hour, afterwards it is cooled to again-78 ℃.Then, in 30 minutes, slowly add the 20ml CH of methacrylaldehyde (14.8mL, 180mmol, 3 equivalents) ₂Cl ₂Solution.Continue to stir after 30 minutes, allow reaction mixture be warming up to 0 ℃ and stirred 1 hour.Under 0 ℃, add phosphate buffered saline buffer (60mL), MeOH (180mL) and the MeOH/35%H of pH 7.0 successively ₂O ₂(2: 1v/v, 180mL).Stir under the room temperature after 3 hours, mixture is cooled to 0 ℃ and use 40%NaHSO again ₃The aqueous solution (80mL) is handled.Vacuum is removed volatile matter and will be contained water and extracts (3 * 200mL) with toluene.The organic layer that merges is washed with 1N HCl (60mL), saturated sodium bicarbonate aqueous solution (60mL) and saturated sodium-chloride water solution (60mL), with dried over mgso, filtration and vacuum concentration, obtain the required alcohol of the little yellow crude product solid residue shape of 28.6g, its sample is passed through purification by flash chromatography (SiO ₂, hexane/AcOEt 3: 1), obtain the pure alcohol of white crystal shape, m.p.99.5-100.0 ℃.

Step 4.2: the crude product alcohol (13.9g) of step 4.1 is dissolved in 50mL CH under argon atmosphere ₂Cl ₂In and be cooled to 0 ℃.Add 2, the 6-lutidine (4.9mL, 42mmol), then with 10 minutes time dropping TBSOTf (7.1mL, 31mmol).Reaction mixture was stirred 30 minutes down at 0 ℃, and order is added 100mL hexane and 45mL 1N HCl afterwards.With waterbearing stratum hexane extraction (2 times).The organic layer that merges is washed with 1N HCl (2 times), saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution,, obtain the crude product product of 17.7g yellow crystals shape then with dried over mgso and vacuum concentration.Behind 20mL hexane recrystallization (interpolation crystal seed), obtain the required TBDMS ether of little yellow crystals shape, m.p.116 ℃.

Embodiment 5: (4R)-and 4-sec.-propyl-5, the 5-phenylbenzene-(N)-[(2R, 3S, 4S)-and 5-hydroxyl-2,4-dimethyl-3-(tertiary butyl-dimethylsilane oxygen base)-pentanoyl]-oxazolidines-2-ketone

Under 23 ℃, with the 3.0mLMeOH solution of the TBDMS ether of 110mg (0.17mmol) step 5.2 in hydrogenation 5 hours under 1 crust atmosphere of hydrogen in the presence of the catalytic amount Pd/C.Reaction mixture is filtered by the cellflock pad, with MeOH washing 3 times, vacuum concentration and carry out flash chromatography (SiO ₂, hexane/EtOAc 5: 1), obtain the title compound (physical data is referring to embodiment 4) of white solid

Step 5.1: with (R)-4-sec.-propyl-5,5-phenylbenzene propionyl base oxazolidine-2-ketone is (referring to step 4.1; 1.00g 7.5mL dichloromethane solution 2.96mmol) is at 0 ℃ of Bu that uses 1.0M down ₂(3.55mL 3.55mmol) handles down in argon atmosphere BOTf solution.In the red-brown mixture of gained, add 0.66mL (3.85mmol) diisopropylethylamine, obtain colourless, clear soln, it was stirred 1 hour down at 0 ℃.Slowly add (S)-3-(4-methoxyl group benzyloxy base)-2-methyl-propionic aldehyde (Aldrich, 616mg, 1.0ml CH 2.96mmol) down at-78 ℃ then ₂Cl ₂Solution.Reaction mixture was stirred 60 minutes under this temperature and stirred 60 minutes down at 0 ℃.At 0 ℃ of phosphate buffered saline buffer (3.0mL), MeOH (8.9mL) and MeOH/30%H that adds pH 7.0 down in proper order ₂O ₂(2: 1v/v, 8.9mL).After at room temperature stirring 1 hour, vacuum is removed volatile matter and will be contained water and extracts (3 times) with TBME.With organic layer 1N HCl, saturated sodium bicarbonate aqueous solution and the saturated NaCl solution washing that merges, with dried over mgso and vacuum concentration.Through chromatogram purification (SiO ₂, heptane/EtOAc 4: 1) after, the required alcohol of colorless oil obtained.

Step 5.2: (96mg 0.18mmol) is dissolved in 5mL CH under argon atmosphere will to derive from the alcohol of step 5.1 ₂Cl ₂In and be cooled to 0 ℃.Add 2, the 6-lutidine (31 μ L, 0.27mmol), then drip TBSOTf (50 μ L, 0.22mmol).Reaction mixture was stirred 45 minutes down at 0 ℃, be poured on the frozen water and and extract (3 times) with TBME.The organic layer that merges is washed with 1N HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution,, obtain the required product of white buttery then with dried over mgso and vacuum concentration.

Embodiment 6: (4R)-and 4-sec.-propyl-5, the 5-phenylbenzene-(N)-[(2R, 3S, 4S)-3, and 5-dihydroxyl-2,4-dimethyl-pentanoyl]-oxazolidines-2-ketone

Under 0 ℃, argon atmosphere, derive from the 130mL THF solution that adds 9-BBN (7.56g, 62.0mmol, 2.5 equivalents) in the 100mL THF solution of vinyl carbinol of step 4.1 with 30 minutes time to 10.2g (25.0mmol).At 0 ℃ after following 10 minutes, allow reaction mixture be warming up to room temperature and stirred 6.5 hours.Mixture is cooled to again-15 ℃ of water-bearing phosphate salt buffer and 35% aqueous hydrogen peroxide solution termination reactions of also using 1: 1 (v/v) EtOH/THF, the pH 7 of the 78mL that respectively does for oneself.After 30 minutes, allow solution be warming up to room temperature once more and stirred 15 hours.Order is added NaHSO ₃40% aqueous solution (210g) and heptane (200mL), and with the waterbearing stratum with heptane extraction (2 * 150mL).With the organic layer that merges with 0.2N NaOH (2 * 100mL), saturated NH ₄The Cl aqueous solution (1 * 100mL) and saturated sodium-chloride water solution (1 * 100mL) washing is with dried over mgso, filter and vacuum concentration.By purification by flash chromatography (SiO ₂, hexane/AcOEt 1: 1), obtain the title compound of 7.38g colorless oil, its crystallization when depositing for 4 ℃ forms m.p. and is 103-104 ℃ solid.

Embodiment 7: (4R)-and 4-sec.-propyl-5, the 5-phenylbenzene-(N)-[(2R, 3S, 4S)-3, and two (tertiary butyls-dimethylsilane oxygen base)-2 of 5-, 4-dimethyl-pentanoyl]-oxazolidines-2-ketone

(1.10g 2.04mmol) is dissolved in 20mL CH under argon atmosphere with the alcohol of embodiment 6 ₂Cl ₂In and be cooled to 0 ℃.Add 2,6-lutidine (0.28mL, 2.45mmol, 1.20 equivalents) then drips TBSOTf (0.49mL, 2.14mmol, 1.05 equivalents).Reaction mixture was stirred 60 minutes, be poured on the 1N HCl and and extract (3 times) with heptane.With the saturated NaHCO of organic layer ₃The aqueous solution and saturated sodium-chloride water solution washing then with dried over mgso and vacuum concentration, obtain the title compound of colorless oil, its crystallization when depositing for 4 ℃, and formation m.p. is 104-105 ℃ a solid.

Embodiment 8: (2S, 3S, 4S)-3, two (tertiary butyls-dimethylsilane oxygen base)-2 of 5-, 4-dimethyl-penta-1-alcohol

Under 0 ℃, with 10 minutes times with 2.0M LiBH ₄THF solution (6.55mL, 13.10mmol) add to embodiment 7 two-(5.36g 8.19mmol) in the solution of 130mL ether and 234 μ L (13.02mmol) water, is warming up to ambient temperature overnight with mixture to TBDMS ether.The chirality assistant agent forms the white crystal precipitation.Under 23 ℃, add 73 μ L (4.06mmol) water and 2.05mL (4.09mmol) 2M LiBH ₄Solution.Continue reaction after 6.5 hours, under 23 ℃, add 73 μ L (4.06mmol) water and 2.05mL (4.09mmol) 2M LiBH again ₄Solution, and the mixture of gained stirred spend the night.By adding 200mL 1N NaOH, then adding 400mL ethyl acetate termination reaction.To be separated and with the waterbearing stratum with twice of 150mL ethyl acetate extraction.The organic phase that merges is washed with salt solution (250mL), with dried over mgso and vacuum concentration.Resistates is suspended in the 80mL heptane, stirred 1.5 hours down and filter at 0 ℃.With resulting filter cake with cold heptane (75mL) washing and at 50 ℃ of following vacuum-dryings, the assistant agent that obtains reclaiming.The filtrate that merges is concentrated, obtain rough colorless oil title compound.

By following process, can from title compound, obtain suitable-(4S, 5R, 6S)-5, two (tertiary butyls-dimethylsilane oxygen base)-2,4 of 7-, 6-trimethylammonium-hept-2-ene"-1-base iodide:

Step 8.1: with 0.455mL (5.30mmol) oxalyl chloride at 20mL CH ₂Cl ₂In solution with the 1.0mL CH of 0.75mL (10.6mmol) DMSO ₂Cl ₂Solution is handled down in-78 ℃.After 15 minutes, (1.0g is 2.65mmol) at 8mL CH to drip title compound with 30 minutes times ₂Cl ₂In solution.Times interpolation Et with 12 minutes ₃(2.3mL 15.9mmol) and with reaction mixture is warming up to room temperature to N.Continue to stir after 30 minutes, add 40mL TBME and the saturated NH of 50mL ₄Cl solution.Separate the waterbearing stratum and use 30mL TBME extracting twice.With the organic layer that merges 50mL salt water washing, with dried over mgso and concentrating under reduced pressure.The oil of remnants is passed through purification by flash chromatography (heptane/ethyl acetate 100: 1.5), obtain the required aldehyde of colorless oil.

¹H-NMR(CDCl ₃，300MHz，300K)δ＝9.67(s，1H)，4.19(dd，J＝6.6，3.2Hz，1H)，3.52(ddd，J＝25.7，10.0，5.7Hz，2H)，2.44-2.47(m，1H)，1.78-1.87(m，1H)，1.07(d，J＝7.0Hz，3H)，0.87(d，J＝7.0Hz，3H)，0.86(s，9H)，0.82(s，9H)，0.03(s，3H)，0.00(2s，6H)，-0.05(s，3H)。

Step 8.2: with 2-[two-(2; 2; the 2-trifluoroethyl)]-phosphono ethyl propionate (0.948g; 2.74mmol; according to Synthesis 1986; the prepared of describing among 16 (11) 1285-1295) and hexaoxacyclooctadecane-6-6 (2.0g, 10.0mmol) solution in 20ml THF with the toluene solution (2.74mmol) of 5.5mL 0.5M KHMDS in-78 ℃ of processing.After 5 minutes, drip aldehyde (1.029g, 2.74mmol) solution in 8ml THF of step 8.1 with 15 minutes times.Faint yellow reaction mixture is continued down to stir 45 minutes at 0 ℃.Add the saturated NH of 20mL TBME and 20mL then ₄Cl solution then adds 10mL water.Layer is separated, and will contain water 90mL TBME extraction.With organic layer salt water washing and the vacuum concentration that merges.Resistates is suspended in the 10mL normal heptane, stirs and filtered then in 10 minutes.Filtrate is concentrated, obtain required cis-ethyl ester.

Step 8.3: (97mg is 0.21mmol) at 5mL CH with the ethyl ester of step 8.2 ₂Cl ₂In solution toluene solution (0.42mL, 0.63mmol, 3.0 equivalents) with 1.5M DIBAH under argon atmosphere handle down in-78 ℃.Allow reaction mixture be warming up to 0 ℃ and stirred 30 minutes, afterwards by adding 10% H ₂SO ₄Aqueous solution termination reaction.The waterbearing stratum is extracted (3 times) with EtOAc.The organic layer that merges is washed with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, then with dried over mgso, filtration and vacuum concentration.By purification by flash chromatography (SiO ₂, hexane/AcOEt 9: 1) and obtain the required vinyl carbinol of white buttery.

Step 8.4: (59mg is 0.14mmol) at 4mL CH with the vinyl carbinol of step 8.3 ₃CN/Et ₂(1: the solution 3v/v) is used PPh to the O mixture under argon atmosphere ₃(55mg, 0.21mmol, 1.5 equivalents), imidazoles (14mg, 0.21mmol, 1.5 equivalents) and iodine (53mg, 0.21mmol, 1.5 equivalents) are handled down in 0 ℃.The yellow suspension of gained was stirred 30 minutes down at 0 ℃, add NaHSO afterwards ₃Saturated aqueous solution.The waterbearing stratum is extracted (3 times) with TBME.The organic layer that merges is washed with 1N HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, then with dried over mgso, filtration and vacuum concentration.By purification by flash chromatography (SiO ₂, hexane/AcOEt 20: 1) and obtain the required allyl iodide of little yellow oily.

Embodiment 9: (4R)-and 4-sec.-propyl-5, the 5-phenylbenzene-(N)-[(2R, 3S, 4S)-and 5-(4-methoxyl group benzyloxy base)-2,4-dimethyl-3-(tertiary butyl-dimethylsilane oxygen base)-pentanoyl]-oxazolidine-2-ketone

(3.61g is 6.69mmol) at 55mL CH with the alcohol of embodiment 4 ₂Cl ₂In solution under argon atmosphere, use SmOTf ₃(160mg, 0.27mmol 4mol%) handle down in 23 ℃.Muddy slightly solution is cooled to-20 ℃ and drip 4-methoxy-benzyl-2,2,2-trichlorine iminodiacetic acid ester (2.27g in 45 minutes time, 8.03mmol 1.20 equivalents are according to Tetrahedron 1999,55, the method preparation described in the 1607-1630) at 55mL CH ₂Cl ₂In solution.Add finish after, the reaction mixture of gained was stirred 30 minutes down at-20 ℃, be warming up to-10 ℃ and use the 50mL water treatment afterwards.Separating layer.Organic layer with 0.5N NaOH (50mL) and saturated sodium-chloride water solution (50mL) washing, is used dried over mgso, filter and vacuum concentration, by purification by flash chromatography (SiO ₂, hexane/AcOEt 5: 1) after obtain the title compound of colorless oil.

¹H-NMR (CDCl ₃, 300MHz, 300K) δ=7.50-7.22 (m, 12H), 6.83-6.78 (m, 2H), 5.39 (d, J=3.3Hz, 1H), 4.00-3.83 (m, 4H), 3.78 (s, 3H), 3.08 (dd, J=9.4,6.5Hz, 1H), 2.72 (dd, J=9.4,7.1Hz, 1H), 1.98 (septet d, J=6.8,3.3Hz, 1H), 1.60 (m, 1H), 1.25 (d, J=6.5Hz, 3H), 0.86 (d, J=7.0Hz, 3H), 0.81 (s, 9H), 0.76 (d, J=6.8Hz, 3H), 0.70 (d, J=7.0Hz, 3H), 0.00 (s, 3H) ,-0.02 (s, 3H).

Embodiment 10: (4R)-and 4-sec.-propyl-5, the 5-phenylbenzene-(N)-[(2R, 3S, 4S)-and 3-hydroxyl-5-(4-methoxyl group benzyloxy base)-2,4-dimethyl-pentanoyl]-oxazolidine-2-ketone

(162mg is 0.25mmol) at 5mL CH with the PMB ether of embodiment 9 ₃Solution among the CN is handled with the 0.5mL 48%HF aqueous solution down at 23 ℃.Stir after 24 hours, extract (3 times) with the saturated sodium bicarbonate aqueous solution termination reaction and with TBME.The organic layer that merges is washed with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, with dried over mgso, filtration and vacuum concentration.By purification by flash chromatography (SiO ₂, heptane/AcOEt 3: 1) after obtain the title compound of colorless oil.

¹H-NMR (CDCl ₃, 300MHz, 300K) δ 7.45-7.05 (m, 12H), 6.85-6.75 (m, 2H), 5.26 (d, J=3.5Hz, 1H), 4.24 (d, J=11.5Hz, 1H), 4.15 (d, J=11.5Hz, 1H), 3.73 (s, 3H), 3.70 (qd, J=6.9,5.4Hz, 1H), 3.32 (m.1H), 3.15 (d, J=5.0Hz, 1H), 3.05 (dd, J=9.3,4.4Hz, 1H), 2.97 (dd, J=9.3,5.1Hz, 1H), 1.90 (septet d, J=6.8,3.5Hz, 1H), and 1.58-1.40 (m, 1H), 1.22 (d, J=6.9Hz, 3H), 0.80 (d, J=7.0Hz, 3H), 0.75 (d, J=7.0Hz, 3H), 0.71 (d, J=6.8Hz, 3H); HRMS (ESI) m/z 568.2671 ([M+Na] ⁺C ₃₃H ₃₉NO ₆Calculated value: 568.2671).

Embodiment 11: (4R)-4-sec.-propyl-5,5-phenylbenzene-(N)-[2-((1S, 3R, 6S)-3-(4-p-methoxy-phenyl)-6-methyl-2, the 4-dioxane oneself-the 1-yl)-(2R)-propionyl]-oxazolidines-2-ketone

Under argon atmosphere, to alcohol (54mg, 1.0mL CH 0.10mmol) of embodiment 10 ₂Cl ₂Add to property 4 molecular sieves (55mg) and DDQ (30mg, 0,13mmol, 1.3 equivalents) successively in 0 ℃ in the solution next time.The deep green reaction mixture of gained was stirred 15 hours down at 0 ℃.Form precipitation.Post precipitation is gone out in filtration, vacuum concentration and PTLC (SiO ₂, 10 * 20cm flat board, heptane/AcOEt 2: 1), obtain the title compound of colorless oil.

¹H-NMR (CDCl ₃, 300MHz, 300K) δ 7.40-7.15 (two m, 8H), 7.22 (d, J=8.7Hz, 2H), 7.07-6.94 (m, 2H), 6.82 (d, J=8.7Hz, 2H), 5.22 (d, J=3.4Hz, 1H), 4.49 (s, 1H), 4.00 (qd, J=6.9,3.4Hz, 1H), 3.85 (dd, J=11.2,4.6Hz, 1H), 3.75 (s, 3H), 3.13 (t, J=11.2Hz, 1H), 3.11 (dd, J=9.7,3.4Hz, 1H), 1.93 (septet d, J=6.8,3.4Hz, 1H), and 1.84-1.70 (m, 1H), 1.19 (d, J=6.9Hz, 3H), 0.85 (d, J=7.0Hz, 3H), 0.72 (d, J=6.8Hz, 3H), 0.53 (d, J=6.8Hz, 3H).

Embodiment 12: (4R)-4-sec.-propyl-5,5-phenylbenzene-(N)-[2-((1S, 3R, 6S)-3-(4-p-methoxy-phenyl)-6-methyl-2, the 4-dioxane oneself-the 1-yl)-(2R)-propionyl]-oxazolidines-2-ketone

150mL CH with the glycol (21.6mmol) of 9.20g embodiment 6 ₂Cl ₂Solution at room temperature uses 2.8g macroporous resin 15 and 4.83g aubepine dimethylacetal (24.9mmol, 1.22 equivalents) to handle successively.The reaction mixture of gained was stirred 2.5 hours, filter afterwards.With the filtrate vacuum concentration, obtain the required acetal of crude product resistates shape.

Embodiment 13: (3R, 4R)-3-hydroxyl-4-((1S, 3R, 6S)-3-(4-p-methoxy-phenyl)-6-methyl-2, the 4-dioxane oneself-the 1-yl)-the valeric acid tertiary butyl ester

Under 0 ℃, to 825 μ L Diisopropylamines (5.84mmol, 2.9 equivalents) at 13mLTHF/HMPA mixture (85: under argon atmosphere, add 3.65mL BuLi (hexane solution of 1.6M, 5.8mmol, 2.9 equivalents) in the solution 15v/v).At 0 ℃ after following 15 minutes, reaction mixture is cooled to-78 ℃ and handle with 810 μ L tert.-butyl acetates (6.0mmol, 3.0 equivalents).At-78 ℃ after following 30 minutes, with the aldehyde (2.00mmol) of 10 minutes times Dropwise 5 29mg step 13.2 in mixture at 9mL THF/HMPA (85: the solution 15v/v).At-78 ℃ after following 15 minutes, reaction mixture is poured over the saturated NH of 40mL ₄On the Cl aqueous solution.The waterbearing stratum is extracted (3 * 40mL) with TBME.With the saturated NH of organic layer that merges ₄The Cl aqueous solution (30mL), saturated sodium-chloride water solution (30mL) washing are with dried over mgso, filtration and vacuum concentration.By purification by flash chromatography (SiO ₂, hexane/AcOEt 4: 1) after, the title compound of colorless oil obtained.

¹H-NMR (CDCl ₃, 300MHz, 300K, the mixture of epimer, ratio=3: 1) and main epimer: δ 7.37 (d, J=8.8Hz, 2H), 6.85 (d, J=8.8Hz, 2H), 5.47 (s, 1H), 4.26-4.19 (m, 1H), 4.09 (dd, J=11.3,4.7Hz, 1H), 3.78 (s, 3H), 3.70 (dd, J=10.0,2.0Hz, 1H), 3.51 (t, J=11.1Hz, 1H), 2.51 (dd, J=15.5,8.2Hz, 1H), 2.39 (dd, J=15.5,5.0Hz, 1H), 1.98-2.17 (m, 1H), 1.92-1.78 (m, 1H), 1.44 (s, 9H), 1.04 (d, J=7.1Hz, 3H), 0.74 (d, J=6.7Hz, 3H); Accessory epimer: δ 7.34 (d, J=8.9Hz, 2H), 6.86 (d, J=8.9Hz, 2H), 5.48 (s, 1H), 4.08 (dd, J=11.3,4.7Hz, 1H), and 4.06-3.97 (m, 1H), 3.91 (dd, J=10.1,1.8Hz, 1H), 3.79 (s, 3H), 3.52 (t, J=11.1Hz, 1H), 2.58 (dd, J=16.0,3.8Hz, 1H), 2.39 (dd, J=16.0,8.7Hz, 1H), 1.98-2.17 (m, 1H), 1.92-1.78 (m, 1H), 1.45 (s, 9H), 0.99 (d, J=7.1Hz, 3H), 0.73 (d, J=6.8Hz, 3H); MS (EI) m/z 783 (5, [2M+Na] ⁺), 403 (100, [M+Na] ⁺), 347 (25, [M+Na-C ₂H ₈] ⁺).

Step 13.1: under-78 ℃, in the 60mL THF solution of the crude product acetal of 12.62g embodiment 11 in argon atmosphere down with 30 minutes time interpolation 62mL 1M LiAlH ₄THF solution (62mmol).-78 ℃ down stir 3 hours after, allow reaction mixture be warming up to 0 ℃ and use 2.4mL water, the 2.4mL 15%NaOH aqueous solution and 7.1mL water treatment successively.Filter the precipitation of removal formation and wash (2 * 10mL) with THF.Collect filtrate and vacuum concentration and begin half of volume to it.Form white precipitate in the concentration process.Add heptane (100mL), form more precipitation.Suspension vacuum-evaporation is begun half of volume to it, stir down at 0 ℃ and filtered then in 30 minutes.With resistates heptane wash (3 * 10mL).Collect filtrate and vacuum concentration, obtain the required alcohol of crude product of yellow oily.

Step 13.2: under-78 ℃, to the 40mL CH of 3.10g oxalyl chloride (24mmol) ₂Cl ₂Under argon atmosphere, drip the 16mL CH of 4.22g DMSO (54mmol) in the solution successively ₂Cl ₂The 30mL CH of the crude product alcohol (6.20g) of solution and step 13.1 ₂Cl ₂Solution.The gained reaction mixture was stirred 30 minutes down at-78 ℃.Then, in compound of reaction, drip 18.5mL diisopropylethylamine (108mmol) and after-78 ℃ are stirred 1 hour down, be warming up to 0 ℃.Add entry (70mL) and with waterbearing stratum CH ₂Cl ₂Extraction (2 * 40mL).(2 * 50mL) washings are with dried over mgso, filter and vacuum concentration with saturated sodium-chloride water solution with the organic layer that merges.Passing through purification by flash chromatography (SiO ₂, heptane/AcOEt 3: 1) after, the required aldehyde of colorless oil obtained.

¹H-NMR(CDCl ₃，300MHz，300K)δ9.76(s，1H)，7.33(d，J＝8.8Hz，2H)，6.86(d，J＝8.8Hz，2H)，5.48(s，1H)，4.15(dd，J＝11.3，4.7Hz，1H)，4.07(dd，J＝10.1，2.50Hz，1H)，3.79(s，3H)，3.58(dd，J＝11.3Hz，1H)，2.58(qd，J＝7.1，2.5Hz，1H)，2.10(ddqd，J＝11.3，10.1，6.7，4.7，Hz，1H)，1.24(d，J＝7.1Hz，3H)，0.81(d，J＝6.7Hz，3H)。

Embodiment 14:

Under-50 ℃, LDA (0.71mmol in stirring, hexane solution preparation under 0 ℃ by 0.77mmol Diisopropylamine and 0.71mmol 1.6M BuLi) under argon atmosphere, adds product (118mg, THF 0.31mmol) (0.30mL) solution of embodiment 13 in THF (0.30mL) solution.Allow reaction mixture be warming up to-10 ℃ and under this temperature, stirred 10 minutes.Then, reaction mixture is cooled to-50 ℃ and under this temperature, stirred 30 minutes.Add product (244mg, 0.42mmol) solution in THF (0.10mL) and HMPA (0.10mL) mixture of step 8.4.Reaction mixture was stirred 2 hours down at-50 ℃, use TBME (2mL) dilution and impouring NH afterwards ₄In the saturated aqueous solution of Cl (2mL).Then, with reaction mixture at NaHCO ₃(2 * 5mL) and TBME (distribute between 2 * 5mL).The organic extract that merges is washed dry (MgSO with NaCl (5mL) ₄) and vacuum concentration.Through SiO ₂Filter (5%EtOAc/ hexane), obtain the product of colorless oil; MS (EI) m/z 801 (100, [M+Na] ⁺).

Embodiment 15:

(350mg adds LiAlH down at-78 ℃ in THF 0.39mmol) (10mL) solution to the crude product product of the step 15.3 in stirring ₄(4.0mL 1M/THF solution, 4.00mmol) and make it in 1.5 hours, be warming up to-10 ℃ gradually.Then, by interpolation MeOH (2mL) termination reaction, and in sodium-potassium tartrate (15mL) and TBME (distribution between 3 * 50mL).With the organic extract drying (MgSO that merges ₄) and vacuum concentration.Obtain the required compound of colorless solid shape through flash chromatography (95%EtOAc/ hexane); IR (KBr): ν _Max2959s, 2930s, 2857s, 1472m, 1462m, 1250s, 1113m, 1083s, 1062s, 1038m, 1019s, 1005w, 856w, 835s, 774s; ¹H-NMR (CDCl ₃, 500MHz, 298K) δ 7.85 (dt, J=9.0,2.0Hz, 2H), 6.88 (dt, J=9.0,2.0Hz, 2H), 5.39 (s, 1H), 5.07 (d, J=10.0Hz, 1H), 4.10 (dd, J=11.0,4.5Hz, 1H), 3.80 (s, 3H), 3.63 (dd, J=5.0,2.0Hz, 1H), 3.62 (dd, J=10.0,5.0Hz, 1H), 3.52 (dd, J=10.0,2.0Hz, 1H), 3.48 (t, J=11.5Hz, 1H), 3.43 (t, J=5.5Hz, 1H), 3.36 (dd, J=10.0,8.0Hz, 1H), 2.51 (m, 1H), 2.34 (t, J=12.0Hz, 1H), 2.06 (m, 1H), 1.99 (m, 1H), 1.88 (td, J=7.0,1.5Hz, 1H), 1.80 (m, 1H), 1.71 (br d, J ≈ 11Hz, 1H), 1.58 (s, 3H), 1.02 (d, J=7.0Hz, 3H), 0.91 (d, J ≈ 7Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.89 (d, J ≈ 7Hz, 3H), 0.889 (s, 9H), 0.76 (d, J=7.0Hz, 3H), 0.75 (d, J=6.50Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02 (s, 9H), 0.01 (s, 3H); ¹³C-NMR (CDCl ₃, 125MHz, 300K) δ 131.8,131.7, and 127.5,114.5,113.6,101.2,83.6,78.6,77.7,73.5,65.5,55.4,41.5,38.3,37.5,35.4,34.0,31.0,26.1,26.0,25.8,23.3,18.6,18.5,16.8,13.8,12.8,12.3,11.0,5.9,-3.3 ,-3.4 ,-3.5 ,-3.6 ,-3.8 ,-5.1; MS (EI) m/z:829 (7, [M+Na] ⁺), 826 (17, [2M+Ca] ²⁺), 377 (90), 313 (100).

Step 15.1: crude product (400mg, CH 0.51mmol) of the embodiment 14 in stirring ₂Cl ₂(10mL) add Et down in-78 ℃ in the solution ₃N (714 μ L, 5.13mmol), add then TBDMSOTf (586 μ L, 2.55mmol).Reaction mixture is warming up to room temperature and stirred 4 hours.Then with reaction mixture at NaHCO ₃(20mL) and CH ₂Cl ₂(distribute between 3 * 50mL).With the organic extract drying (MgSO that merges ₄) and vacuum concentration.Through SiO ₂Filter (5%EtOAc/ hexane), obtain the crude product product of colorless oil; MS (EI) m/z 915 (100, [M+Na] ⁺).

Step 15.2: (561mg adds LiAlH down in-78 ℃ in THF 0.63mmol) (15mL) solution to the crude product of the step 15.1 in stirring ₄(6.30mL 1M/THF solution, 6.30mmol).Reaction mixture was warming up to-15 ℃ gradually in 1 hour.Then, make reaction mixture stopped reaction and vigorous stirring at room temperature by the aqueous solution (30mL) that adds sodium-potassium tartrate carefully.After 30 minutes, separating layer and with the waterbearing stratum with TBME extraction (3 * 100mL).With the organic layer drying (Na that merges ₂SO ₄) and vacuum concentration.Through SiO ₂Filter (5-30%EtOAc/ hexane), obtain the required alcohol of colorless oil; MS (EI) m/z 923 (100, [M+Na] ⁺).

Step 15.3: crude product (400mg, CH 0.49mmol) of the step 15.2 in stirring ₂Cl ₂(10mL) in the solution, under room temperature, add Et ₃N (338 μ L, 2.43mmol) and methylsulfonyl chloride (58 μ L, 0.74mmol).After 20 hours, with mixture at NaHCO ₃(15mL) and CH ₂Cl ₂(distribute between 3 * 20mL).With the organic extract drying (Na that merges ₂SO ₄) and vacuum concentration.Through SiO ₂Filter (10-20%EtOAc/ hexane), obtain the crude product of colorless oil; MS (EI) m/z 891 (100, [M+Na] ⁺).

Claims (17)

1. the preparation method of the alkene of the replacement of following formula I

Wherein

R ₁, R ₂And R ₃Be hydroxyl protecting group or hydrogen independently of one another, and

R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl,

In described method, with the sulphonate reduction of following formula (II),

R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₄Have suc as formula defined implication and R in the I compound ₅Be alkyl or aryl unsubstituted or that alkyl replaces,

And subsequently, if necessary, with one, two or all protecting group R ₁, R ₂And R ₃Slough.

2. the preparation method of the alkene of the replacement of following formula I

Wherein

R ₁, R ₂And R ₃Be hydroxyl protecting group or hydrogen independently of one another, and

R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl,

In described method, at first the carboxylicesters with Formula Il I reduces

R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₆Be alkyl or aryl alkyl and R ₄Have suc as formula defined implication in the I compound, then with the alcohol of resulting following formula I V

R wherein ₁, R ₂, R ₃And R ₄Has defined implication in the formula III compound, with the compound reaction of following formula V

R ₅SO ₂Hal (V)

R wherein ₅Be that alkyl or aryl and Hal unsubstituted or that alkyl replaces represent halogen, the sulphonate with resulting Formula Il further reduces then

Wherein

R ₁, R ₂, R ₃And R ₄Have defined implication and R in the carboxylicesters of formula III ₅Be alkyl or aryl unsubstituted or that alkyl replaces,

And if necessary, by methods known in the art with one, two or all protecting group R ₁, R ₂And R ₃Slough.

3. the preparation method of the carboxylicesters of Formula Il I

Wherein

R ₁And R ₂Be hydroxyl protecting group, these protecting groups can be identical or different, or hydrogen, R ₃Be hydrogen, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, and R ₆Be the alkyl or aryl alkyl,

In described method, with the allyl halide of following formula VI

R wherein ₁And R ₂Having in the carboxylicesters as formula III defined implication and X is halogen, reacts in the presence of alkali with the carboxylicesters of following formula VII

R wherein ₃, R ₄And R ₆Have defined implication in the carboxylicesters as formula III, and subsequently, if necessary, with one or all protecting group R ₁Or R ₂Slough.

4. claim 1,2 or 3 each described method, wherein R ₁And R ₂Be identical and R ₁, R ₂And R ₃It is the silyl protecting group.

5. the sulphonate of Formula Il

R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, and R ₅Be alkyl or aryl unsubstituted or that alkyl replaces.

6. the sulphonate of the described formula II of claim 5, wherein R ₁And R ₂Be identical, R ₁, R ₂And R ₃Be benzyl or silyl protecting group, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, and R ₅It is the phenyl that low alkyl group or low alkyl group replace.

7. the sulphonate of the described formula II of claim 5, wherein R ₁And R ₂And R ₃Be t-butyldimethylsilyl, R ₄Be unsubstituted or mono-substituted phenyl of lower alkoxy and R ₅By low alkyl group or the mono-substituted phenyl of low alkyl group.

8. the carboxylicesters of Formula Il I

R wherein ₁And R ₂Be hydroxyl protecting group, these protecting groups can be identical or different, R ₃Be hydroxyl protecting group or hydrogen, T ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl, and T ₆It is the alkyl or aryl alkyl.

9. the carboxylicesters of the described formula III of claim 8, wherein R ₁And R ₂Be identical, R ₁, R ₂And R ₃Be silyl protecting group and R ₆It is low alkyl group.

10. the alcohol of following formula I V

R wherein ₁, R ₂And R ₃All are hydroxyl protecting groups, these protecting groups can be identical or different and R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl.

11. the carboxylicesters of following formula VII

R wherein ₃Be hydrogen, R ₄Be unsubstituted or the replacement of alkoxy list or dibasic phenyl and R ₆It is the alkyl or aryl alkyl.

12. following formula VIII De oxazolidone

Wherein

Ph represents phenyl, and

R ₁And R ₂Be silyl protecting group, hydrogen or unsubstituted or replaced or dibasic benzyl independently of one another, perhaps by the lower alkoxy list

R ₁And R ₂Lump together the methylene radical that the expression phenyl replaces, described phenyl is lower alkoxy list replacement or dibasic.

13. following formula I X De oxazolidone

Wherein Ph represents phenyl, and R ' and R ₂Be silyl protecting group, hydrogen or unsubstituted or replaced or dibasic benzyl by the lower alkoxy list independently of one another, condition is radicals R ' and R ₂The two one of be the silyl protecting group.

14. the δ of following formula X-penta lactol

R wherein ₂It is hydroxyl protecting group.

15. the alcohol of following formula XI

R wherein ₁And R ₂All represent the silyl protecting group.

16. the carboxylicesters of the sulphonate of each described formula II of claim 5-7, claim 8 or 9 described formula IIIs, the alcohol of the described formula IV of claim 10 or the purposes of the described carboxylic acid of claim 11 in the method for production discodermolide or discodermolide analogue.

17. the preparation method of the ether of following formula XXVI

Wherein

R ₁Be that the alkoxy list replaces or dibasic benzyl,

R ₂Expression hydroxyl protecting group or hydrogen, and

R ₁₀It is N-oxazolidinyl unsubstituted or that replaced by alkyl, benzyl or phenyl;

OR _e, R wherein _eBe alkyl or benzyl, or

N (R _a) ₂, R wherein _aBe alkyl or benzyl,

It is characterized in that compound with following formula XXVII

Radicals R wherein ₂And R ₁₀Suc as formula defining in the XXVI compound, in the presence of trifluoromethanesulfonic acid samarium or Ytterbiumtriflate, react with the trichlorine iminodiacetic acid ester of following formula XVII

Wherein m is 1 or 2,

And subsequently, if necessary, with protecting group R ₂Slough.